Anthelmintics

ABSTRACT

Anthelmintically active compounds of formula I are described ##STR1## in which R 1  is hydrogen, halogen, C 1  -C 2  alkyl, C 1  -C 2  thioalkyl, C 1  -C 2  haloalkyl, nitro, C 1  -C 2  alkoxy, or the group SO n  R in which R is C 1  -C 2  alkyl or phenyl and n is 0, 1 or 2; 
     R 2  is hydrogen, halogen, C 1  -C 2  alkyl, C 1  -C 2  haloalkyl, C 1  -C 2  haloalkoxy or C 1  -C 2  alkoxy; 
     R 3  is hydrogen or C 1  -C 2  alkyl; 
     R 4  is hydrogen or C 1  -C 2  alkyl; 
     R 5  is hydrogen, halogen or C 1  -C 5  alkyl; 
     R 6  is hydrogen, halogen or C 1  -C 5  alkyl; 
     R 7  is hydrogen, halogen, C 1  -C 2  alkyl, nitro, C 1  -C 2  haloalkyl, C 1  -C 2  haloalkoxy or C 1  -C 2  alkoxy; 
     R 8  is hydrogen, halogen, C 1  -C 2  alkyl, C 1  -C 2  haloalkyl, C 1  -C 2  haloalkoxy or C 1  -C 2  alkoxy; 
     R 9  is hydrogen, halogen, C 1  -C 2  alkyl, C 1  -C 2  haloalkyl, C 1  -C 2  haloalkoxy or C 1  -C 2  alkoxy; 
     R 10  is hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 2  haloalkyl, C 1  -C 2  alkylthio, C 3  -C 6  cycloalkyl or cyano; 
     R 11  is hydrogen, halogen, C 1  -C 6  alkyl, C 1  -C 2  haloalkyl, C 1  -C 2  alkylthio or C 3  -C 6  cycloalkyl; 
     R 12  is hydrogen or halogen; and Y is ═CH-- or ═N-; including the physiologically tolerable acid additon salts thereof, and also the preparatin and use thereof and novel intermediates.

The present invention relates to novel substituted anthranilic acidderivatives having anthelmintic activity, to anthelmintic compositionsbased on those novel active ingredients and to the use of the activeingredients and compositions for controlling helminths, especiallynematodes, cestodes and trematodes, in warm-blooded animals, especiallymammals and preferably domestic animals and productive livestock. Theinvention also relates to the preparation of the active ingredients andcompositions and to novel intermediates for the preparation of theactive ingredients.

The novel anthranilic acid derivatives have the following formula I##STR2## in which R₁ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂thioalkyl, C₁ -C₂ haloalkyl, nitro, C₁ -C₂ alkoxy, or the group SO_(n) Rin which R is C₁ -C₂ alkyl or phenyl and n is 0, 1 or 2;

R₂ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₃ is hydrogen or C₁ -C₂ alkyl;

R₄ is hydrogen or C₁ -C₂ alkyl;

R₅ is hydrogen, halogen or C₁ -C₅ alkyl;

R₆ is hydrogen, halogen or C₁ -C₅ alkyl;

R₇ is hydrogen, halogen, C₁ -C₂ alkyl, nitro, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₈ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₉ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₁₀ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio, C₃ -C₆ cycloalkyl or cyano;

R₁₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio or C₃ -C₆ cycloalkyl;

R₁₂ is hydrogen or halogen; and

Y is ═CH-- or ═N--; including the physiologically tolerable acidaddition salts thereof.

To mention is a subgroup of compounds of the formula I in which

R₁ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, nitro, C₁ -C₂alkoxy, or the group SO_(n) R in which R is C₁ -C₂ alkyl or phenyl and nis 0, 1 or 2;

R₂ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₃ is hydrogen or C₁ -C₂ alkyl;

R₄ is hydrogen or C₁ -C₂ alkyl;

R₅ is hydrogen, halogen or C₁ -C₅ alkyl;

R₆ is hydrogen, halogen or C₁ -C₅ alkyl;

R₇ is hydrogen, halogen, C₁ -C₂ alkyl, nitro, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₈ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₉ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₁₀ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio, C₃ -C₆ cycloalkyl or cyano;

R₁₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio or C₃ -C₆ cycloalkyl;

R₁₂ is hydrogen or halogen; and

Y is ═CH-- or ═N--; including the physiologically tolerable acidaddition salts thereof.

By the term alkyl on its own or as a component of another substituent,depending on the number of carbon atoms indicated there is to beunderstood, within the scope of the present invention, for example thefollowing straight-chain and branched groups: methyl, ethyl, n-propyl,isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, etc. Haloalkyl onits own or as a component of haloalkoxy is a mono- to per-halogenatedalkyl substituent, such as, for example, CH₂ Cl, CHCl₂, CCl₃, CH₂ F,CHF₂, CF₃, CH₂ Br, CHBr₂, CBr₃, CH₂ I, CI₃, CHClF, CHBrCl, CFBrCl, C₂F₅, CH₂ CH₂ Cl, CHClCH₃, C₂ Cl₅, CHFCHCl₂ etc., preferably CF₃. Byhalogen there is to be understood throughout the specification fluorine,chlorine, bromine or iodine, preferably fluorine, chlorine or bromine,but more especially chlorine.

A preferred sub-group of compounds of formula I is formed by thosecompounds in which

R₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₂ and Y are as defined for formula I;

R₅ is hydrogen, halogen or C₁ -C₃ alkyl;

R₆ is hydrogen, halogen or C₁ -C₃ alkyl;

R₁₀ is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio, cyclopropyl or cyano; and

R₁₁ is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio or cyclopropyl; including the physiologically tolerable acidaddition salts thereof.

A further preferred group is formed by compounds of formula I in which

R₁ is hydrogen, halogen, methyl, methoxy or thiomethyl;

R₂ is hydrogen, methyl or halogen;

R₃ is hydrogen, methyl or ethyl;

R₄ is hydrogen, methyl or ethyl;

R₅ is hydrogen, halogen or C₁ -C₄ alkyl;

R₆ is hydrogen, halogen or C₁ -C₄ alkyl;

R₇ is hydrogen, halogen, methyl, methoxy, CF₃ or nitro;

R₈ is hydrogen or halogen;

R₉ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂haloalkoxy or C₁ -C₂ alkoxy;

R₁₀ and R₁₁, independently of one another, are each hydrogen, halogen,C₁ -C₄ alkyl, methylthio, trifluoromethyl, CF₂ CCl₂ F, cyclopropyl orcyano; R₁₂ is hydrogen or halogen; and

Y is ═CH-- or ═N--, wherein the pyridinoxy or pyrimidinoxy substituentis bonded by way of the 3- or 4-position of the phenyl ring.

Other groups of preferred compounds of formula I are formed by thosecompounds in which R₁ is 5-halogen (preferably chlorine) or 4-halogen(preferably chlorine), R₂ is hydrogen and the remaining substituents areas defined for formula I or as defined in the above-mentioned preferredgroups.

Within the scope of formula I and the mentioned sub-groups preference isgiven to those compounds in which the substituent R₁ is in the5-position of the phenyl group.

Preferred compounds of formula I include the following individualcompounds:

5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide];

5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-anilide];

5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethylpyridin-2-yloxy)-anilide];

5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-tert.-butylpyrimidin-2-yloxy)-anilide];

3,5-dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide];

3,5-dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(5-trifluoromethylpyridin-2-yloxy)-anilide].

The preferred compounds also include4-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-anilide].

It has been found that the novel compounds of formula I according to theinvention surprisingly have a very favourable spectrum of activityagainst helminths that are parasites of animals, especially those thatparasites warm-blooded animals, especially mammals. The compounds offormula I can be used very successfully against nematodes as well ascestodes and trematodes. They are distinguished in particular by thefact that they are fully effective also against benzimidazole-resistant,especially thiabendazole-resistant, helminths ("thiabendazole" denotesthe active ingredient 2-(thiazol-4-yl)-benzimidazole).

The compounds of formula I are prepared by

(A) reacting a compound of formula II with a benzenesulfonic acid halideof formula III ##STR3## or (B) reacting a compound of formula IV with acompound of formula V ##STR4## wherein the substituents R₁ to R₁₂ and Yin formulae II, III, IV and V are as defined for formula I, X in formulaIII is halogen, preferably chlorine or bromine, especially chlorine, andA in formula IV is halogen (preferably chlorine or bromine), OH, or aleaving group capable of reacting with an amino group, and, whereappropriate, subsequently alkylating a compound of formula II in whichboth R₃ and R₄ are hydrogen or only one of them is hydrogen.

In the reactions (II) with (III) and (IV) with (V) there may be used asbases, for example, tertiary amines (such as triethylamine,trimethylamine, tripropylamine, N-methylpiperidine,1,4-diazabicyclo(2,2,2)octane etc.), pyridine and pyridine bases (suchas 4-dimethylaminopyridine, 4-pyrrolidylaminopyridine, picolines,lutidine etc.), and also alkaline earth metal or preferably alkali metalalcoholates of lower alkanols (such as, for example, sodium or potassiumalcoholates of methanol, propanol, ethanol, n-butanol, isobutanol,tert.-butanol etc.). Pyridine is preferred.

Suitable solvents or diluents are, for example, the following aproticsolvents: aliphatic and aromatic hydrocarbons, such as benzene, toluene,xylenes, petroleum ether; halogenated hydrocarbons, such aschlorobenzene, methylene chloride, ethylene chloride, chloroform, carbontetrachloride, tetrachloroethylene; ethers and ethereal compounds, suchas dialkyl ethers (diethyl ether, diisopropyl ether, tert.-butylmethylether etc.), anisole, dioxane and tetrahydrofuran; nitriles, such asacetonitrile and propionitrile; some N,N-alkylated amides, such asdimethylformamide; dimethyl sulfoxide; ketones, such as acetone, diethylketone and methyl ethyl ketone, and mixtures of such solvents. In manycases the base itself can act as solvent.

The reaction temperatures are usually from -20° to +150° C., preferablyfrom 0° to +100° C. In cases where A in formula IV is OH, a condensationagent, such as dicyclohexylcarbodiimide, may be added.

The described preparation process, including all the subsidiary steps,forms an important component of the present invention.

The compounds of formula II are novel and the present invention relatesto them since the main characteristics of the end products are alreadyapparent in them.

The compounds of formula II can be prepared by several processes; forexample they can be prepared from a compound of formula VI ##STR5## (i)by hydrogenation in the presence of a suitable hydrogenation catalystand, where appropriate, by subsequent N-alkylation to introduce thesubstituent R₄, or

(ii) by chemical reduction, or

(iii) by reacting a compound of formula VII with a compound of formula V##STR6## in which formulae the substituents R₁, R₂, R₃, R₄, R₅, R₆, R₁₀,R₁₁ and R₁₂ and Y are as defined for formula I.

The reactions (i) and (ii) can take place under normal pressure and arepreferably carried out in the presence of an inert organic solvent ordiluent, preferably in the presence of one of the above-mentioned ethersor ethereal compounds, an ester, such as ethyl acetate, propyl acetateor butyl acetate, or an alcohol, especially an alkanol, such asmethanol, ethanol, propanol etc. The reactions are generally carried outat temperatures of from 0° to 80° C., preferably from 10° to 50° C.

A suitable catalyst for process (i) is, for example, Rh/C or Raneynickel.

The chemical reduction (ii) can be carried out, for example, withSn-(II)-chloride/HCl.

Reaction (iii) is preferably carried out in the presence of an inertorganic polar solvent, such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, dioxane, butanone, THF ordimethoxyethane. The reaction temperatures are from -10° to +150° C.,preferably from 0° to 100° C.

The nitro compounds of formula VI are also novel and the presentinvention relates to them.

Compounds of formula VI can be prepared by reacting compounds of formulaVIII with compounds of formula (V) ##STR7## in which A in formula VIIIis OH, a reactive leaving group, such as halogen (preferably chlorine orbromine), or an activated ester radical, such as, for example,alkoxycarbonyloxy. These reactions are preferably carried out in thepresence of an inert organic solvent, such as benzene, toluene, CH₂ Cl₂,ether, DMF, DMSO, THF, acetonitrile or acetone, advantageously in thepresence of a base, such as triethylamine, pyridine or picoline, at from-20° C. to 150° C., preferably from 0° C. to 50° C. When A=OH, thereaction can also be carried out in the presence of a condensationagent, such as, for example, dicyclohexylcarbodiimide.

Compounds of formula V are known or can be prepared, for example, byreacting a compound of formula IX ##STR8## with a compound of formula X##STR9## in which R₃, R₅, R₆, R₁₀, R₁₁ and R₁₂ and also Y are as definedfor formula I and Q is a customary leaving group. The reactiontemperatures are usually from 0° C. to 200° C., preferably from 10° C.to 150° C., and the reaction is carried out in inert polar solvents,such as, for example, N,N-dimethylformamide, N,N-dimethylacetamide orpreferably dimethyl sulfoxide, with the addition of an inorganic base,such as sodium carbonate, potassium carbonate or, preferably, potassiumhydroxide. The water of reaction formed in these reactions can beremoved from the reaction mixture by means of an entrainer, such as, forexample, CH₂ Cl₂, toluene or benzene.

Q in formula X is either one of the customary leaving groups, forexample halogen, especially chlorine, bromine or iodine; or asulfonyloxy group, especially benzenesulfonyloxy, para-tosyloxy or loweralkylsulfonyloxy, preferably mesyloxy.

Compounds of formula VII are preferably obtained by oxidising compoundsof formula XI ##STR10##

This preparation process is known, inter alia, from DE 29 25 175 andAngewandte Chemie 92, 196 (1980). The compounds of formula VII (R₄ =H)obtained from such a process can, where appropriate, be alkylated at thenitrogen atom, for example according to J. Heterocycl. Chem. 565 (1975).

The compounds of formula XI and processes for their preparation areknown, and they can be prepared according to a method familiar to theperson skilled in the art, cf. Houben/Weyl vol. 7/4, p. 5 ff.

Compounds of formula IV (A=OH) can be obtained by hydrolysing compoundsof formula XII or XIII ##STR11## in which B is OCH₃ or OC₂ H₅. The saidhydrolysis is preferably effected with an inorganic base, such as NaOHor KOH, in the presence of a solvent, such as water and/or an alcohol,preferably methanol or ethanol, cf. Houben/Weyl, 9, p. 609 ff.

Compounds of formula IV (A=reactive leaving group) can be preparedaccording to methods familiar to the person skilled in the art, forexample from compounds of formula IV (A=OH).

The compounds of formula XII are novel and the present invention extendsalso to them.

The compounds of formulae XII and XIII can be obtained by reactingcompounds of formula XIV ##STR12## in which B, R₁ and R₂ are as definedhereinbefore, with compounds of formula III; when position 3 incompounds of formula XIV is occupied, mixtures of compounds of formulaXII and XIII may result, although it is chiefly sulfonimides of formulaXII that are obtained. When the 3-position in compounds of formula XIVis free, almost exclusively compounds of formula XIII are obtained. Thesaid reactions are preferably carried out under the conditions indicatedfor reaction A (II+III→I).

The preparation of compounds of formula XIV can be carried outanalogously to known methods, for example according to Tetrahedron 33,217 (1977) and DE-3,001,579.

The starting compounds of formulae III, VIII, X, XI, XIII and XIV areknown, or can be prepared analogously to the known compounds.

The invention also includes a method for the prophylactic protection ofanimals against parasitic helminths which comprises administering thecompounds of formula I or the active ingredient formulations to theanimals as an additive to feed or to drinks, or alternatively in solidor liquid form orally, by injection or by means of the pour-on method.

Of the endoparasites occurring in warm-blooded animals, it isspecifically helminths that cause great damage. Animals infested bythese parasites may not only suffer from retarded growth but may alsohave considerable physiological defects, which may even result in death.The development of therapeutic compositions that are suitable forcontrolling helminths and their stages of development and for providingprotection against infestation by such parasites is therefore of greatimportance. Especially dangerous worm-related disorders are thosebrought about by nematodes, cestodes and trematodes parasitising thegastro-intestinal tract and other organs, especially in ruminants, suchas sheep, cattle and goats, and also horses, pigs, red deer, dogs, catsand fowl.

The damage caused by helminthiases can be considerable where there ischronic and especially epidemic occurrence of worm-related disorders inherds of animals. The damage manifests itself inter alia in reductionsin productivity, reduced resistance and increased mortality. Control andprevention of helminthiases is therefore seen as an urgent task in orderto avoid or reduce such damage which is serious especially from theeconomic standpoint.

In the present description there is to be understood by the term"helminths" especially parasitic worms that belong to thePlatyhelminthes (cestodes, trematodes) and Nemathelminthes (nematodesand related species), that is to say tapeworms, sucker worms androundworms of the gastro-intestinal tract and other organs (for exampleliver, lungs, kidneys, lymph vessels, blood etc.). Although a number ofsubstances having anthelmintic activity are known that have beenproposed for controlling various species of helminth, these have notproved completely satisfactory either because at a tolerable dose it isnot possible to make full use of their spectrum of activity or becauseat therapeutically effective doses they exhibit undesired side effectsor properties. In this respect, the resistance to certain classes ofsubstance occurring more and more today is also increasinglysignificant. For example, it is true that "Albendazol", which has beendescribed in the literature (British Pat. No. 1464326; Am. J. Vet. Res.38, 1425-1426 (1977); Am. J. Vet. Res. 37, 1515-1516 (1976); Am. J. Vet.Res. 38, 807-808 (1977); Am. J. Vet. Res. 38, 1247-1248 (1977)), has alimited spectrum of anthelmintic activity in ruminants. Its activityagainst benzimidazole-resistant nematodes and adult liver flukes,however, is unsatisfactory, since in particular the pathogenicallyimportant immature migrating forms of the latter are not affected bydoses tolerated by the host animal.

It has surprisingly been found that the compounds of formula I not only,as has already been mentioned, have an intensive anthelmintic activitywith a broad spectrum of action against nematodes, cestodes andtrematodes, but also are favourable as regards their toxicity towarm-blooded animals.

The novel compounds of formula I according to the invention aresuitable, for example, for controlling parasitic nematodes of the orders(according to K. I. Skrajabin)

Rhabditida,

Ascaridida,

Spirurida,

Trichocephalida,

or for controlling cestodes of the orders (according to Wardle & McLeod)

Cyclophyllidae,

Pseudophyllidae,

or for controlling trematodes of the order

Digenea,

in domestic animals and productive livestock, such as cattle, sheep,goats, horses, pigs, cats, dogs and fowl. They may be administered tothe animals either as a single dose or repeatedly, the singleadministrations preferably being from 1 to 500 mg per kg of body weightdepending on the species of animal. Protracted administration in manycases results in an improved action or may permit the use of smallertotal doses.

The compositions according to the invention are prepared by so bringingthe compounds of formula I into contact with liquid and/or solidformulation adjuvants by mixing and/or grinding in stages that anoptimum display of the anthelmintic activity of the formulation,conformable to the application, is achieved.

The formulation stages can be supplemented by kneading, granulating(granulates) and optionally compressing (pellets).

Suitable formulation adjuvants are, for example, solid carriers,solvents and, where appropriate, surface-active substances(surfactants).

The following formulation adjuvants are used to prepare the compositionsaccording to the invention:

Solid carriers such as, for example, kaolin, talcum, bentonite, sodiumchloride, calcium phosphate, carbohydrates, cellulose powder, cottonseedmeal, polyethylene glycol ether, where appropriate, binders such as, forexample, gelatin, soluble cellulose derivatives, if desired with theaddition of surface-active substances, such as ionic or non-ionicdispersants; and also natural mineral fillers, such as calcite,montmorillonite or attapulgite. In order to improve the physicalproperties it is also possible to add highly dispersed silicic acid orhighly dispersed absorbent polymers. Suitable granulated adsorptivecarriers are porous types, for example pumice, broken brick, sepioliteor bentonite; and suitable nonsorbent carriers are, for example, calciteor sand. In addition, a great number of pregranulated materials ofinorganic or organic nature can be used, e.g. especially dolomite orpulverised plant material.

Suitable solvents are: aromatic hydrocarbons, preferably the fractionscontaining 8 to 12 carbon atoms, e.g. xylene mixtures or substitutednaphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate,aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols andglycols and their ethers and esters, such as ethanol, ethylene glycol,ethylene glycol monomethyl or monoethyl ether, ketones such ascyclohexanone, strongly polar solvents such as N-methyl-2-pyrrolidone,dimethyl sulfoxide or dimethylformamide, as well as vegetable oils orepoxidised vegetable oils, such as epoxidised coconut oil or soybeanoil, and water.

Depending on the nature of the compound of formula I to be formulated,suitable surface-active compounds are non-ionic, cationic and/or anionicsurfactants having good emulsifying, dispersing and wetting properties.The term "surfactants" will also be understood as comprising mixtures ofsurfactants.

Both so-called water-soluble soaps and also water-soluble syntheticsurface-active compounds are suitable anionic surfactants.

Suitable soaps are the alkali metal salts, alkaline earth metal salts orunsubstituted or substituted ammonium salts of higher fatty acids (C₁₀-C₂₂), e.g. the sodium or potassium salts of oleic or stearic acid, orof natural fatty acid mixtures which can be obtained e.g. from coconutoil or tallow oil.

Frequently, so-called synthetic surfactants are used, especially fattysulfonates, fatty sulfates, sulfonated benzimidazole derivatives oralkylarylsulfonates.

The fatty sulfonates or sulfates are usually in the form of alkali metalsalts, alkaline earth metal salts or unsubstituted or substitutedammonium salts and contain a C₈ -C₂₂ alkyl radical which also includesthe alkyl moiety of acyl radicals, e.g. the sodium or calcium salt oflignosulfonic acid, of dodecylsulfate or of a mixture of fatty alcoholsulfates obtained from natural fatty acids. These compounds alsocomprise the salts of sulfated and sulfonated fatty alcohol/ethyleneoxide adducts. The sulfonated benzimidazole derivatives preferablycontain 2 sulfonic acid groups and one fatty acid radical containing 8to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium,calcium or triethanolamine salts of dodecylbenzenesulfonic acid,dibutylnaphthalenesulfonic acid, or of a condensate ofnaphthalenesulfonic acid and formaldehyde.

Also suitable as formulation adjuvants are corresponding phosphates,e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenolwith 4 to 14 moles of ethylene oxide, or phospholipids.

Non-ionic surfactants are preferably polyglycol ether derivatives ofaliphatic or cycloaliphatic alcohols, saturated or unsaturated fattyacids and alkylphenols, said derivatives containing 3 to 30 glycol ethergroups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moietyand 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.

Further suitable non-ionic surfactants are the water-soluble adducts ofpolyethylene oxide with polypropylene glycol,ethylenediaminopolypropylene glycol and alkylpolypropylene glycolcontaining 1 to 10 carbon atoms in the alkyl chain, which adductscontain 20 to 250 ethylene glycol ether groups and 10 to 100 propyleneglycol ether groups. These compounds usually contain 1 to 5 ethyleneglycol units per propylene glycol unit.

Examples of non-ionic surfactants are nonylphenolpolyethoxyethanols,castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts,tributylphenoxypolyethoxyethanol, polyethylene glycol andoctylphenoxypolyethoxyethanol.

Fatty acid esters of polyoxyethylene sorbitan, e.g. polyoxyethylenesorbitan trioleate, are also suitable non-ionic surfactants.

Cationic surfactants are preferably quaternary ammonium salts whichcontain, as N-substituent, at least one C₈ -C₂₂ alkyl radical and, asfurther substituents, unsubstituted or halogenated lower alkyl, benzylor hydroxy-lower alkyl radicals. The salts are preferably in the form ofhalides, methylsulfates or ethylsulfates, e.g. stearyltrimethylammoniumchloride or benzyldi(2-chloroethyl)ethylammonium bromide.

The surfactants customarily employed in the art of formulation aredescribed, inter alia, in the following publications:

"Mc Cutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp.,Ridgewood N.J., 1981;

Stache, H., "Tensid-Taschenbuch", Carl Hanser Verlag, Munich/Vienna,1981.

Suitable binders for tablets and boli are chemically modified naturalpolymer substances that are soluble in water or alcohol, such as starch,cellulose or protein derivatives (e.g. methylcellulose,carboxymethylcellulose, ethylhydroxyethylcellulose, proteins such aszein, gelatin and the like) and synthetic polymers, such as, forexample, polyvinyl alcohol, polyvinylpyrrolidone etc.. The tablets alsocontain fillers (e.g. starch, microcrystalline cellulose, sugar, lactoseetc.), glidants and disintegrators.

If the anthelmintic compositions are in the form of feed concentrates,then the carriers used are, for example, performance feed, feed grain orprotein concentrates. In addition to the active ingredients, such feedconcentrates or compositions may contain additives, vitamins,antibiotics, chemotherapeutic agents or pesticides, especiallybacteriostatics, fungistatics or coccidiostatics, or also hormonepreparations, substances having an anabolic activity, or substances thatpromote growth, influence the meat quality of slaughtered animals or areuseful to the organism in some other way. If the compositions or theactive ingredients of formula I contained therein are added directly tothe feed or to the herd drinks, then the prepared feed or the prepareddrink preferably contains the active ingredients in a concentration ofapproximately from 0.0005 to 0.02 percent by weight (5-200 ppm).

The compositions according to the invention can be administered to theanimals to be treated perorally, parenterally, subcutaneously ortopically, the compositions being in the form of solutions, emulsions,suspensions (drenches), powders, tablets, boli and capsules.

The anthelmintic compositions according to the invention generallycontain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight,of a compound of formula I, and from 99.9 to 1% by weight, preferablyfrom 99.9 to 5% by weight, of a solid or liquid adjuvant, including from0 to 25% by weight, preferably from 0.1 to 25% by weight, of asurfactant.

Whereas commercial products will preferably be formulated asconcentrates, the end user will normally employ dilute formulations.

The compositions may also contain further auxiliaries such asstabilisers, antifoams, viscosity regulators, binders, tackifiers aswell as other active ingredients for obtaining special effects.

The present invention relates also to such anthelmintic compositionsemployed by the end user.

The following Examples serve to illustrate the invention withoutimplying any limitation thereof.

PREPARATION EXAMPLES IN ACCORDANCE WITH PROCESS A 1.1. Preparation of5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide]. (a)5-Chloro-2-nitrobenzoyl chloride

A mixture of 80.6 g of 5-chloro-2-nitrobenzoic acid and 58.2 ml ofthionyl chloride is heated at 90° C. for 2 hours. The excess thionylchloride is then distilled off in vacuo. 87.1 g of5-chloro-2-nitrobenzoyl chloride are obtained.

(b) 5-Chloro-2-nitrobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide]

A solution of 8.0 g of4-[3-chloro-5-trifluoromethylpyridyl-2-oxy)-aniline and 5.2 ml oftriethylamine in 50 ml of methylene chloride is added dropwise, at 0°C., to a solution of 5.8 g of 5-chloro-2-nitrobenzoyl chloride in 50 mlof methylene chloride. After the mixture has been stirred at roomtemperature for 2 hours, approximately 80% of the solvent is removed ina rotary evaporator. The resulting crystal mass is stirred with 100 mlof diethyl ether, and the resulting crystals are washed with 1N HClsolution and H₂ O and are again stirred with 100 ml of diethyl ether.9.6 g of 5-chloro-2-nitrobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] having a meltingpoint of 216°-218° C. are obtained.

(c) 2-Amino-5-chlorobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide]

8.0 g of 5-chloro-2-nitrobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are dissolved in90 ml of tetrahydrofuran and the solution is hydrogenated for 6 hours atroom temperature under a hydrogen atmosphere in the presence of 4 g of5% rhodium/carbon. The reaction mixture is then filtered and the solventis removed by distillation. The resulting crude product is stirred withdiethyl ether. 5.5 g of 2-amino-5-chlorobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained inthe form of white crystals (m.p. 180°-184° C.).

(d) 5-Chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide]

2.0 g of 4-chlorobenzenesulfonic acid chloride are added to a solutionof 3.8 g of 5-chloro-2-aminobenzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] in 8.6 ml ofpyridine at 0° C. After the reaction mixture has been stirred for 16hours at room temperature, 300 ml of methylene chloride are added andthe resulting solution is then washed with 100 ml each of 1N HCl, H₂ O,saturated NaHCO₃ solution and saturated NaCl solution. The organic phaseis then dried with MgSO₄ and concentrated by evaporation. The crudeproduct obtained is purified by stirring in diethyl ether. In thismanner 3.8 g of 5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained inthe form of white crystals (m.p. 191°-193° C.).

IN ACCORDANCE WITH PROCESS B 2.1. Process for the preparation of3,5-dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide] (a)3,5-Dichloro-2-[di-(4-chlorophenylsulfonyl)-amino]-benzoic acid ethylester

138.0 g of 4-chlorobenzenesulfonic acid chloride are added in portions,at room temperature, to a solution of 50.0 g of 3,5-dichloroanthranilicacid ethyl ester in 210 ml of dry pyridine. The reaction mixture isheated to 80°-90° C. and stirred for 28 hours at that temperature tocomplete the reaction. After cooling, the reaction mixture is pouredonto ice/water and acidified with 2N hydrochloric acid. The sticky, oilyprecipitate is dissolved in diethyl ether, and the aqueous phase isremoved. The organic phase is washed with water and saturated sodiumchloride solution. After drying over magnesium sulfate, the ether isevaporated off and the crystals remaining are stirred in a mixture ofdiethyl ether/hexane 4:1. The crystals, which are filtered off, weigh87.3 g after drying and correspond to the title compound (m.p. 148°-150°C.).

(b) 3,5-Dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid

A suspension of 27.0 g of3,5-dichloro-2-[di-(4-chlorophenylsulfonyl)-amino]-benzoic acid ethylester, 139 ml of 2N sodium hydroxide solution and 140 ml of ethanol isboiled at reflux for 6 hours, the solid gradually dissolving. After thereaction mixture has cooled, the precipitated crystals are filtered offand dissolved in 400 ml of water. 400 ml of methanol are added,acidification with 2N hydrochloric acid is carried out, and theprecipitated crystals are filtered off. 12.3 g of the title compound(m.p. 188°-190° C.) are obtained.

(c) 3,5-Dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide]

4.0 g of 3,5-dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acidare suspended in 10 ml of thionyl chloride. The reaction mixture isboiled at reflux for 3 hours. After the excess thionyl chloride has beendistilled off, the residue is twice concentrated by evaporation from 20ml of toluene. The solid crude acid chloride so obtained is dissolved in30 ml of methylene chloride. A solution of 3.3 g of4-(4-trifluoromethyl)-6-cyclopropylpyrimidin-2-yloxy)-aniline [m.p.75°-78° C.], 2 ml of triethylamine and 20 ml of methylene chloride isslowly added dropwise to this solution while cooling with ice/water.After 24 hours at room temperature, the precipitated solid is filteredoff and washed with a small amount of methylene chloride. The crudeproduct is washed with 2N hydrochloric acid and water, then dried andstirred with 50 ml of diethyl ether. 2.27 g of the title compound (m.p.273°-276° C.) are obtained. It is possible to isolate a further 2.06 gof the title compound by working up the concentrated mother liquors inthe above manner.

The compounds listed in the following can be prepared analogously to thedescribed methods. The lists are not of a limiting nature.

                                      TABLE 1                                     __________________________________________________________________________    Compounds of formula Ia                                                        ##STR13##                                                                                                        Posi-                                                                         tion                   Prepa-             Comp.                               of                M.p. ration             No. R.sub.1                                                                             R.sub.2                                                                            R.sub.3   R.sub.4                                                                  R.sub.5                                                                           R.sub.6                                                                           R.sub.7                                                                            R.sub.8                                                                          Het                                                                              Het            [°C.]                                                                       variant            __________________________________________________________________________    1.1 5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR14##     199-201                                                                            A                  1.2 5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR15##     191-193                                                                            A                  1.3 5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR16##     162-165                                                                            A                  1.4 5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR17##     203-204                                                                            A                  1.5 5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR18##     273-276                                                                            B                  1.6 5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR19##     285-286                                                                            B                  1.7 5-SCH.sub.3                                                                         H    H  H H   H   4-Cl H  4                                                                                 ##STR20##     167-170                                                                            A                  1.8 5-Cl  H    H  H H   H   4-NO.sub.2                                                                         H  4                                                                                 ##STR21##          A                  1.9 6-CH.sub.3                                                                          3-OCH.sub.3                                                                        H  H H   H   4-Cl H  4                                                                                 ##STR22##          A                  1.10                                                                              5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR23##          A                  1.11                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR24##     258-260                                                                            B                  1.12                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR25##     309-312                                                                            B                  1.13                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR26##     264-265                                                                            B                  1.14                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR27##     228-231                                                                            B                  1.15                                                                              5-Cl  3-Cl H  H 2-iso- propyl                                                                     H   4-Cl H  4                                                                                 ##STR28##     250-252                                                                            B                  1.16                                                                              5-Cl  3-Cl H  H 2-CH.sub.3                                                                        6-CH.sub.3                                                                        4-Cl H  4                                                                                 ##STR29##     282-285                                                                            B                  1.17                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR30##     264-266                                                                            B                  1.18                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR31##     256-259                                                                            B                  1.19                                                                              5-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR32##     175-177                                                                            B                  1.20                                                                              5-CF.sub.3                                                                          H    H  H H   H   4-Cl H  4                                                                                 ##STR33##          B                  1.21                                                                              3-CF.sub.3                                                                          H    H  H H   H   4-Cl H  4                                                                                 ##STR34##     278-281                                                                            A                  1.22                                                                              4-OCH.sub.3                                                                         6-CH.sub.3                                                                         H  H H   H   4-Cl H  4                                                                                 ##STR35##          B                  1.23                                                                              5-S(O)CH.sub.3                                                                      H    H  H H   H   4-Cl H  4                                                                                 ##STR36##          Subse- quent                                                                  oxida- tion        1.24                                                                              5-SO.sub.2 CH.sub.3                                                                 H    H  H H   H   4-Cl H  4                                                                                 ##STR37##          Subse- quent                                                                  oxida- ation       1.25                                                                              5-SCH.sub.3                                                                         H    H  H H   H   4-Cl H  4                                                                                 ##STR38##     158-161                                                                            A                  1.26                                                                              5-F   H    H  H H   H   4-Cl H  4                                                                                 ##STR39##     218-220                                                                            A                  1.27                                                                              5-F   3-F  H  H H   H   4-Cl H  4                                                                                 ##STR40##     278-279                                                                            A                  1.28                                                                              5-Cl  3-Cl H  H H   H   4-Cl H  4                                                                                 ##STR41##     258-261                                                                            B                  1.29                                                                              5-Cl  3-Cl H  H 4-CH.sub.3                                                                        H   4-Cl H  3                                                                                 ##STR42##     244-246                                                                            B                  1.30                                                                              5-Cl  H    CH.sub.3  H                                                                        H   H   4-Cl H  4                                                                                 ##STR43##     169-170                                                                            B                  1.31                                                                              5-Cl  H    H  H 2-F H   4-Cl H  4                                                                                 ##STR44##     145-147                                                                            B                  1.32                                                                              5-Cl  H    H  H 2-F H   4-Cl H  4                                                                                 ##STR45##     155-157                                                                            B                  1.33                                                                              5-Cl  H    H   CH.sub.3                                                                       H   H   4-Cl H  4                                                                                 ##STR46##     176-178                                                                            A                  1.34                                                                              5-Cl  H    H  H H   H   4-Cl 3-Cl                                                                             4                                                                                 ##STR47##          A                  1.35                                                                              5-Cl  H    H  H 4-Cl                                                                              H   4-Cl H  3                                                                                 ##STR48##     188-190                                                                            A                  1.36                                                                              5-Cl  H    H  H 4-Cl                                                                              H   4-F  H  3                                                                                 ##STR49##     214-218                                                                            A                  1.37                                                                              5-OCH.sub.3                                                                         H    H  H H   H   4-Cl H  4                                                                                 ##STR50##          B                  1.38                                                                              5-Cl  H    H  H H   H   4-OCH.sub.3                                                                        H  4                                                                                 ##STR51##          A                  1.39                                                                              4-Cl  H    H  H H   H   4-Cl H  4                                                                                 ##STR52##     197-200                                                                            B                  1.40                                                                              6-CH.sub.3                                                                          H    H  H H   H   4-CH.sub.3                                                                         H  4                                                                                 ##STR53##     207-211                                                                            B                  1.41                                                                              5-F   H    H  H H   H   4-Cl H  4                                                                                 ##STR54##     231-233                                                                            A                  1.42                                                                              5-F   3-F  H  H H   H   4-Cl H  4                                                                                 ##STR55##     245-247                                                                            A                  1.43                                                                              5-Cl  4-Cl H  H H   H   4-Cl H  4                                                                                 ##STR56##                             __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Intermediates of formula                                                       ##STR57##                                                                    Comp.                 Position         M.p.                                   No. R.sub.1                                                                            R.sub.2                                                                          R.sub.3                                                                         R.sub.4                                                                          R.sub.6                                                                          R.sub.5                                                                         of Het                                                                             Het         [°C.]                           __________________________________________________________________________    2.1 5-Cl H  H H  H  H 4                                                                                   ##STR58##  180-184                                2.2 5-Cl H  H H  H  H 4                                                                                   ##STR59##  175-177                                2.3 5-Cl H  H H  H  H 4                                                                                   ##STR60##  182-183                                2.4 5-Cl H  H H  H  H 4                                                                                   ##STR61##  173-174                                2.5 5-Cl H  H CH.sub.3                                                                         H  H 4                                                                                   ##STR62##  190-192                                2.6 4-Cl H  H H  H  H 4                                                                                   ##STR63##  218-220                                2.7 5-SCH.sub.3                                                                        H  H H  H  H 4                                                                                   ##STR64##  159-162                                2.8 5-SCH.sub.3                                                                        H  H H  H  H 4                                                                                   ##STR65##  157-161                                2.9 3-CF.sub.3                                                                         H  H H  H  H 4                                                                                   ##STR66##  165-167                                2.10                                                                              5-Cl H  H H  4-Cl                                                                             H 3                                                                                   ##STR67##  193-194                                2.11                                                                              5-F  H  H H  H  H 4                                                                                   ##STR68##  166-168                                2.12                                                                              5-F  H  H H  H  H 4                                                                                   ##STR69##  168-170                                2.13                                                                              5-F  3-F                                                                              H H  H  H 4                                                                                   ##STR70##  196-198                                2.14                                                                              5-F  3-F                                                                              H H  H  H 4                                                                                   ##STR71##  189-190                                __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    Intermediates of formula                                                       ##STR72##                                                                    Comp.              Position         M.p.                                      No. R.sub.1                                                                            R.sub.2                                                                          R.sub.3                                                                         R.sub.5                                                                         R.sub.6                                                                          of Het                                                                             Het         [°C.]                              __________________________________________________________________________    3.1 5-Cl H  H H H  4                                                                                   ##STR73##  216-218                                   3.2 5-Cl H  H H H  4                                                                                   ##STR74##  188-192                                   3.3 5-Cl H  H H H  4                                                                                   ##STR75##  203-205                                   3.4 5-Cl H  H H H  4                                                                                   ##STR76##  202-203                                   3.5 4-Cl H  H H H  4                                                                                   ##STR77##  214-216                                   3.6 4-Cl H  H H H  4                                                                                   ##STR78##  195-198                                   3.7 5-Cl H  H H 4-Cl                                                                             3                                                                                   ##STR79##  168-170                                   3.8 5-SCH.sub.3                                                                        H  H H H  4                                                                                   ##STR80##  204-207                                   3.9 5-SCH.sub.3                                                                        H  H H H  4                                                                                   ##STR81##  221-224                                   3.10                                                                              5-F  H  H H H  4                                                                                   ##STR82##  181-182                                   3.11                                                                              5-F  H  H H H  4                                                                                   ##STR83##  206-207                                   3.12                                                                              5-F  3-F                                                                              H H H  4                                                                                   ##STR84##  217-218                                   3.13                                                                              5-F  3-F                                                                              H H H  4                                                                                   ##STR85##  219-220                                   __________________________________________________________________________

2. FORMULATION EXAMPLES (throughout, percentages are by weight)

    ______________________________________                                        2.1. Emulsifiable concentrates                                                                   a)        b)     c)                                        ______________________________________                                        active ingredient from Table 1                                                                   25%       40%    50%                                       calcium dodecylbenzenesulfonate                                                                   5%        8%     6%                                       castor oil polyethylene glycol                                                                    5%       --     --                                        ether (36 moles of ethylene oxide)                                            tributylphenol polyethylene glycol                                                               --        12%     4%                                       ether (30 moles of ethylene oxide)                                            cyclohexanone      --        15%    20%                                       xylene mixture     65%       25%    20%                                       ______________________________________                                    

Emulsions of any desired concentration can be produced from suchconcentrates by dilution with water.

    ______________________________________                                        2.2. Solutions     a)     b)      c)    d)                                    ______________________________________                                        active ingredient from Table 1                                                                   80%    10%     5%    95%                                   ethylene glycol monomethyl ether                                                                 20%    --      --    --                                    polyethylene glycol                                                                              --     70%     --    --                                    (mol. wt. 400)                                                                N-methyl-2-pyrrolidone                                                                           --     20%     --    --                                    epoxidised coconut oil                                                                           --     --      1%     5%                                   petroleum fraction --     --      94%   --                                    (boiling range 160-190° C.)                                            ______________________________________                                    

The solutions are suitable for use in the form of microdrops.

    ______________________________________                                        2.3. Granulates      a)      b)                                               ______________________________________                                        active ingredient from Table 1                                                                     5%      10%                                              kaolin               94%     --                                               highly dispersed silicic acid                                                                      1%      --                                               attapulgite          --      90%                                              ______________________________________                                    

The active ingredient is dissolved in methylene chloride, the solutionis sprayed onto the carrier, and the solvent is subsequently evaporatedoff in vacuo. Such granulates can be admixed with the animal feed.

    ______________________________________                                        2.4. Dusts           a)      b)                                               ______________________________________                                        active ingredient from Table 1                                                                     2%      5%                                               highly dispersed silicic acid                                                                      1%      5%                                               talcum               97%     --                                               kaolin               --      90%                                              ______________________________________                                    

Ready-for-use dusts are obtained by intimately mixing the carriers withthe active ingredient.

    ______________________________________                                        2.5. Powder mixture dispersible in water                                                            a)      b)     c)                                       ______________________________________                                        active ingredient from Table 1                                                                      25%     50%    75%                                      sodium lignosulfonate 5%       5%    --                                       oleic acid            3%      --      5%                                      sodium diisobutylnaphthalene-                                                                       --       6%    10%                                      sulfonate                                                                     octylphenol polyethylene glycol                                                                     --       2%    --                                       ether (7-8 moles of ethylene oxide)                                           highly dispersed silicic acid                                                                       5%      10%    10%                                      kaolin                62%     27%    --                                       ______________________________________                                    

The active ingredient is thoroughly mixed with the adjuvants and themixture is thoroughly ground in a suitable mill, affording wettablepowders which can be diluted with water to give suspensions of thedesired concentration.

    ______________________________________                                        2.6. Emulsifiable concentrate                                                                     a)      b)       c)                                       ______________________________________                                        active ingredient from Table 1                                                                    10%     8%       60%                                      octylphenol polyethylene glycol                                                                    3%     3%        2%                                      ether (4-5 moles of ethylene oxide)                                           castor oil polyethylene glycol                                                                     4%     5%        4%                                      ether (35 moles of ethylene oxide)                                            cyclohexanone       30%     40%      15%                                      xylene mixture      50%     40%      15%                                      ______________________________________                                    

Emulsions of any desired concentration can be produced from thisconcentrate by dilution with water.

    ______________________________________                                        2.7. Dusts            a)     b)                                               ______________________________________                                        active ingredient from Table 1                                                                       5%    8%                                               talcum                95%    --                                               kaolin                --     92%                                              ______________________________________                                    

Ready-for-use dusts are obtained by mixing the active ingredient withthe carrier and grinding the mixture on a suitable mill.

    ______________________________________                                        2.8. Granulate                                                                ______________________________________                                        active ingredient from Table 1                                                                     10%                                                      sodium lignosulfonate                                                                               2%                                                      carboxymethylcellulose                                                                              1%                                                      kaolin               87%                                                      ______________________________________                                    

The active ingredient is mixed and ground with the adjuvants, and themixture is subsequently moistened with water. The mixture is extrudedand then dried in a stream of air.

    ______________________________________                                        2.9. Granulate                                                                ______________________________________                                        active ingredient from Table 1                                                                      3%                                                      polyethylene glycol (mol. wt. 200)                                                                  3%                                                      kaolin                94%                                                     ______________________________________                                    

The finely ground active ingredient is uniformly applied, in a mixer, tothe kaolin moistened with polyethylene glycol. Non-dusty coatedgranulates are obtained in this manner.

    ______________________________________                                        2.10. Suspension concentrate                                                  ______________________________________                                        active ingredient from Table 1                                                                       40%                                                    ethylene glycol        10%                                                    nonylphenol polyethylene glycol                                                                      6%                                                     ether (15 moles of ethylene oxide)                                            sodium lignosulfonate  10%                                                    carboxymethylcellulose 1%                                                     37% aqueous formaldehyde solution                                                                    0.2%                                                   silicone oil in the form of a 75%                                                                    0.8%                                                   aqueous emulsion                                                              water                  32%                                                    ______________________________________                                    

The finely ground active ingredient is intimately mixed with theadjuvants, giving a suspension concentrate from which suspensions of anydesired concentration can be obtained by dilution with water.

    ______________________________________                                        2.11. Pellets or boli                                                         ______________________________________                                        an active ingredient from Table 1                                                                   33.00%                                                  methylcellulose       0.80%                                                   highly dispersed silicic acid                                                                       0.80%                                                   cornstarch            8.40%                                                   II                                                                            crystalline lactose   22.50%                                                  cornstarch            17.00%                                                  microcrystalline cellulose                                                                          16.50%                                                  magnesium stearate    1.00%                                                   ______________________________________                                    

I The methylcellulose is stirred into water and allowed to swell; thesilicic acid is stirred in and the mixture is made into a homogeneoussuspension. The active ingredient and cornstarch are mixed and theaqueous suspension is incorporated into this mixture which is kneaded toa paste. The mass so obtained is granulated through a 12M sieve anddried.

II All 4 adjuvants are thoroughly mixed.

III Phases I and II are mixed together and compressed to pellets orboli.

3. BIOLOGICAL EXAMPLES

The anthelmintic activity is demonstrated by way of the following tests:

3.1. Trial with sheep infested with nematodes such as Haemonchuscontortus and Trichostrongylus colubriformis

The active ingredient is administered in the form of a suspension usinga stomach probe or by intraruminal injection to sheep that havepreviously been artificially infested with nematodes, such as Haemonchuscontortus and Trichostrongylus colubriformis. 1 to 3 animals are usedfor each dose per trial. Each sheep is treated only once with a singledose.

A first evaluation is made by comparing the number of worm eggs excretedin the faeces of the sheep before and after treatment.

Seven to ten days after treatment the sheep are sacrificed anddissected. The evaluation is carried out by counting the worms remainingin the intestine after the treatment. Sheep simultaneously and similarlyinfested but untreated are used as a control or comparison.

Compounds from Table 1 administered to sheep in the form of a suspensionat a dose of 50 mg/kg body weight or lower effect a reduction innematode infestation of 90% or more compared with untreated but infestedcomparison groups. Compounds of formula I, such as, for example, No. 1.1and 1.2, produce a reduction in nematode infestation of more than 90%even at a dose of 20 mg/kg body weight.

3.2. Trial with sheep infested with Fasciola hepatica

The active ingredient is administered in the form of a suspension usinga stomach probe or by intraruminal injection to sheep that havepreviously been artificially infested with Fasciola hepatica. 3 animalsare used for each dose per trial. Each sheep is treated only once with asingle dose.

A first evaluation is made by comparing the number of worm eggs excretedin the faeces of the sheep before and after treatment.

Three to four weeks after treatment the sheep are sacrificed anddissected. The evaluation is carried out by counting the liver flukesremaining in the gall-bladder ducts after the treatment. Sheepsimultaneously and similarly infested but untreated are used as acontrol or comparison. The difference in the number of liver flukescounted in the two groups gives the degree of effectiveness of the testcompound.

Suspensions with active ingredients from Table I produce good results,that is to say a decrease in liver fluke infestation of at least 90% ata dose of 50 mg/kg body weight or lower.

What is claimed is:
 1. Compounds of formula I ##STR86## in which R₁ ishydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ thioalkyl, C₁ -C₂ haloalkyl,nitro, C₁ -C₂ alkoxy, or the group SO_(n) R in which R is C₁ -C₂ alkylor phenyl and n is 0, 1 or 2;R₂ is hydrogen, halogen, C₁ -C₂ alkyl, C₁-C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂ alkoxy; R₃ is hydrogen or C₁-C₂ alkyl; R₄ is hydrogen or C₁ -C₂ alkyl; R₅ is hydrogen, halogen or C₁-C₅ alkyl; R₆ is hydrogen, halogen or C₁ -C₅ alkyl; R₇ is hydrogen,halogen, C₁ -C₂ alkyl, nitro, C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁-C₂ alkoxy; R₈ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁-C₂ haloalkoxy or C₁ -C₂ alkoxy; R₉ is hydrogen, halogen, C₁ -C₂ alkyl,C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂ alkoxy; R₁₀ is hydrogen,halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ alkylthio, C₃ -C₆cycloalkyl or cyano; R₁₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂haloalkyl, C₁ -C₂ alkylthio or C₃ -C₆ cycloalkyl; R₁₂ is hydrogen orhalogen; and Y is ═N--; including the physiologically tolerable acidaddition salts thereof.
 2. A compound according to claim 1, in whichR₁is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, nitro, C₁ -C₂alkoxy, or the group SO_(n) R in which R is C₁ -C₂ alkyl or phenyl and nis 0, 1 or 2; and R₂ to R₁₂ and Y are as defined in claim
 1. 3. Acompound according to claim 1, in whichR₁, R₂, R₃, R₄, R₇, R₈, R₉, R₁₂and Y are as defined for formula I; R₅ is hydrogen, halogen or C₁ -C₃alkyl; R₆ is hydrogen, halogen or C₁ -C₃ alkyl; R₁₀ is hydrogen,halogen, C₁ -C₄ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ alkylthio, cyclopropylor cyano; and R₁₁ is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₂ haloalkyl,C₁ -C₂ alkylthio or cyclopropyl; including the physiologically tolerableacid addition salts thereof.
 4. A compound according to claim 2, inwhichR₁ is hydrogen, halogen, methyl, methoxy or thiomethyl; R₂ ishydrogen, methyl or halogen; R₃ is hydrogen, methyl or ethyl; R₄ ishydrogen, methyl or ethyl; R₅ is hydrogen, halogen or C₁ -C₄ alkyl; R₆is hydrogen, halogen or C₁ -C₄ alkyl; R₇ is hydrogen, halogen, methyl,methoxy, CF₃ or nitro; R₈ is hydrogen or halogen; R₉ is hydrogen,halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂alkoxy; R₁₀ and R₁₁, independently of one another, are each hydrogen,halogen, C₁ -C₄ alkyl, methylthio, trifluoromethyl, CF₂ CCl₂ F,cyclopropyl or cyano; R₁₂ is hydrogen or halogen; and Y is ═N--, whereinthe pyrimidinoxy substituent is bonded by way of the 3- or 4-position ofthe phenyl ring.
 5. A compound according to claim 1, in whichR₁ is5-halogen or 4-halogen; R₂ is hydrogen; R₃ is hydrogen or C₁ -C₂ alkyl;R₄ is hydrogen or C₁ -C₂ alkyl; R₅ is hydrogen, halogen or C₁ -C₅ alkyl;R₆ is hydrogen, halogen or C₁ -C₅ alkyl; R₇ is hydrogen, halogen, C₁ -C₂alkyl, nitro, C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂ alkoxy; R₈is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxyor C₁ -C₂ alkoxy; R₉ is hydrogen, halogen, C₁ -C₂ alkyl, C₁ -C₂haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂ alkoxy; R₁₀ is hydrogen, halogen,C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ alkylthio, C₃ -C₆ cycloalkyl orcyano; R₁₁ is hydrogen, halogen, C₁ -C₆ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂alkylthio or C₃ -C₆ cycloalkyl; R₁₂ is hydrogen or halogen; and Y is═N--; including the physiologically tolerable acid addition saltsthereof.
 6. A compound according to claim 5, in whichR₁ is 5-chlorine or4-chlorine; R₂ is hydrogen; R₃ is hydrogen, methyl or ethyl; R₄ ishydrogen, methyl or ethyl; R₅ is hydrogen, halogen or C₁ -C₄ alkyl; R₆is hydrogen, halogen or C₁ -C₄ alkyl; R₇ is hydrogen, halogen, methyl,methoxy, CF₃ or nitro; R₈ is hydrogen or halogen; R₉ is hydrogen,halogen, C₁ -C₂ alkyl, C₁ -C₂ haloalkyl, C₁ -C₂ haloalkoxy or C₁ -C₂alkoxy; R₁₀ and R₁₁, independently of one another, are each hydrogen,halogen, C₁ -C₄ alkyl, methylthio, trifluoromethyl, CF₂ CCl₂ F,cyclopropyl or cyano; R₁₂ is hydrogen or halogen; and Y is ═N--, whereinthe pyrimidinoxy substituent is bonded by way of the 3- or 4-position ofthe phenyl ring.
 7. A compound according to claim 1, selected from theseries:5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide];5-chloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-tert.-butylpyrimidin-2-yloxy)-anilide];3,5-dichloro-2-[(4-chlorophenylsulfonyl)-amino]-benzoic acid[4-(4-trifluoromethyl-6-cyclopropylpyrimidin-2-yloxy)-anilide].
 8. Acomposition comprising an anthelmintically effective amount of acompound according to claim 1 together with a physiologically tolerable,inert formulation adjuvant.
 9. A method of controlling helminths in awarm-blooded animal, which comprises administering prophylactically orcuratively to the warm-blooded animal an anthelmintically effectiveamount of a compound of according to claim
 1. 10. A compositioncomprising an anthelmintically effective amount of a compound accordingto claim 2 together with a physiologically tolerable, inert formulationadjuvant.
 11. A composition comprising an anthelmintically effectiveamount of a compound according to claim 3 together with aphysiologically tolerable, inert formulation adjuvant.
 12. A compositioncomprising an anthelmintically effective amount of a compound accordingto claim 5 together with a physiologically tolerable, inert formulationadjuvant.
 13. A composition comprising an anthelmintically effectiveamount of a compound according to claim 6 together with aphysiologically tolerable, inert formulation adjuvant.
 14. A compositioncomprising an anthelmintically effective amount of a compound accordingto claim 7 together with a physiologically tolerable, inert formulationadjuvant.
 15. A method of controlling helminths in a warm-bloodedanimal, which comprises administering prophylactically or curatively tothe warm-blooded animal an anthelmintically effective amount of acompound according to claim
 2. 16. A method of controlling helminths ina warm-blooded animal, which comprises administering prophylactically orcuratively to the warm-blooded animal an anthelmintically effectiveamount of a compound according to claim
 3. 17. A method of controllinghelminths in a warm-blooded animal, which comprises administeringprophylactically or curatively to the warm-blooded animal ananthelmintically effective amount of a compound according to claim 5.18. A method of controlling helminths in a warm-blooded animal, whichcomprises administering prophylactically or curatively to thewarm-blooded animal an anthelmintically effective amount of a compoundaccording to claim
 6. 19. A method of controlling helminths in awarm-blooded animal, which comprises administering prophylactically orcuratively to the warm-blooded animal an anthelmintically effectiveamount of a compound according to claim
 7. 20. A compound of the formula##STR87## in which R₁, R₂, R₃, R₅, R₆, R₁₀, R₁₁ and R₁₂ are as definedin claim 1, and R₁₃ is --NO₂ or --NHR₄ wherein R₄ is also as defined inclaim 1.